Implants and methods for treating inflammation-mediated conditions of the eye

ABSTRACT

Methods for treating inflammation-mediated conditions of the eye are described, comprising: implanting into the vitreous of the eye of an individual a bioerodible implant comprising a steroidal anti-inflammatory agent and a bioerodible polymer, wherein the implant delivers the agent to the vitreous in an amount sufficient to reach a concentration equivalent to at least about 0.05 μg/ml dexamethasone within about 48 hours and maintains a concentration equivalent to at least about 0.03 μg/ml dexamethasone for at least about three weeks.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 14/691,079, filed on Apr. 20, 2015, which is a continuation ofU.S. patent application Ser. No. 13/886,465, filed on May 3, 2013, whichis a continuation of U.S. patent application Ser. No. 13/494,591, filedon Jun. 12, 2012, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 13/271,451, filed Oct. 12, 2011, and now U.S. Pat.No. 8,242,099, which is a continuation of U.S. patent application Ser.No. 12/646,522, filed Dec. 23, 2009, and now U.S. Pat. No. 8,063,031,which is a continuation of U.S. patent application Ser. No. 10/671,816,filed Sep. 25, 2003, now abandoned, which is a continuation of U.S.patent application Ser. No. 09/693,008, filed Oct. 20, 2000, and nowU.S. Pat. No. 6,726,918, which claims priority to U.S. ProvisionalApplication Ser. No. 60/216,236, filed Jul. 5, 2000. The entiredisclosure of the aforementioned U.S. Patent Applications areincorporated herein by reference.

TECHNICAL FIELD

This invention relates to methods for treating inflammation-mediatedconditions of the eye by implanting into the vitreous of the eye abioerodible implant comprising a steroidal anti-inflammatory agent and abioerodible polymer. Specifically, these methods may be used in theprotection and treatment of tissues damaged by or susceptible to damageby inflammation-mediated conditions such as uveitis, by providingtherapeutic levels of an anti-inflammatory agent to the vitreous of theeye.

BACKGROUND ART

Glucocorticoids are an important part of treatment in severe anterior,intermediate, posterior, and panuveitis. A major problem with presentdrug therapy is the inability to achieve adequate intraocular drugconcentration. In particular, uveitis is well known for its longduration due in part to the difficulties associated with poorintraocular penetration of topical medications into the posteriorsegment (Bloch-Michel E. (1992). “Opening address: intermediateuveitis,” In Intermediate Uveitis. Dev Ophthalmol. W. R. F. Böke et al.eds., Basel: Karger, 23:1-2; Pinar, V. Intermediate uveitis.MassaChusetts Eye & Ear Infirmary Immunology Service at<http://www.immunology.meei.harvard.edu/imed.htm> (visited in 1998);Rao, N. A. et al. (1997). “Intraocular inflammation and uveitis” InBasic and Clinical Science Course. Section 9 (1997-1998) San Francisco:American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Böke, W.(1992). “Clinical picture of intermediate uveitis,” In IntermediateUveitis, Dev Ophthalmol, W. R. F. Böke et al. eds., Basel: Karger,23:20-7; Cheng C-K et al. (1995). “Intravitreal sustained-releasedexamethasone device in the treatment of experimental uveitis,” InvestOphthalmol Vis Sci. 36:442-53). Systemic glucocorticoid administrationmay require prolonged exposure of high plasma concentrations(administration of 1 mg/kg/day for 2-3 weeks) so that therapeutic levelscan be achieved in the eye (Pinar, V. “Intermediate uveitis,”Massachusetts Eye & Ear Infirmary Immunology Service at<http://www.immunology.meei.harvard.edu/imed.htm> (visited in 1998)).These high drug plasma levels often lead to systemic side effects suchas hypertension, hyperglycemia, increased susceptibility to infection,peptic ulcers, psychosis, and other complications (Cheng C-K et al,(1995). “intravitreal sustained-release dexamethasone device in thetreatment of experimental uveitis,” Invest Ophthaimol Vis Sci.36:442-53; Schwartz, B. (1966). “The response of ocular pressure tocorticosteroids,” Ophthalmol Clin North Am 6:929-89; Skalka, H. W. etal. (1980). “Effect of corticosteroids on cataract formation,” ArchOphthalmol 98:1773-7; Renfro, L. et al. (1992). “Ocular effects oftopical and systemic steroids,” Dermatologic Clinics 10:505-12). Inaddition, overall drug delivery to the eye may be poor due to the shortdrug plasma half-life limiting exposure into intraocular tissues. Themost efficient way of delivering drug to the posterior segment is toplace it directly in the vitreous (Maurice, D. M. (1983).“Micropharmaceutics of the eye,” Ocular Inflammation Ther 1:97-102; Lee,V. H. L. et al. (1989). “Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby,Vol. 1, pp. 483-98; Olsen, T. W. et al. (1995). “Human scleralpermeability: effects of age, cryotherapy, transscleral diode laser, andsurgical thinning,” Invest Ophthalmol Vis Sci 36:1893-1903).Intravitreal injections have shown promising results, however, due tothe short intraocular half-life of glucocorticoids (approximately 3hours), intravitreal injections must be repeated to maintain drug levelswhich increases the potential for side effects such as retinaldetachment, endophthalmitis, and cataract (Maurice, D. M. (1983).“Micropharmaceutics of the eye,” Ocular Inflammation Ther 1:97-102;Olsen, T. W. et al, (1995). “Human scleral permeability: effects of age,cryotherapy, transscleral diode laser, and surgical thinning,” InvestOphthalmol Vis Sci 36:1893-1903; Kwak, H. W. and D'Amico, D. J. (1992).“Evaluation of the retinal toxicity and pharmacokinetics ofdexamethasone after intravitreal injection,” Arch Ophthalmol110:259-66). Topical, systemic, and periocular glucocorticoid treatmentmust be monitored closely due to toxicity and the long-term side effectsassociated with chronic systemic drug exposure sequelae (Rao, N. A. etal. (1997). “Intraocular inflammation and uveitis” In Basic and ClinicalScience Course. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). “Theresponse of ocular pressure to corticosteroids,” Ophthaimol Clin NorthAm 6:929-89; Skalka, H. W. and Pichal, J. T. (1980). “Effect ofcorticosteroids on cataract formation,” Arch Ophthalmol 98:1773-7;Renfro, L and Snow, J. S. (1992). “Ocular effects of topical andsystemic steroids,” Dermatologic Clinics 10:505-12; Bodor, N. et al.(1992). “A comparison of intraocular pressure elevating activity ofloteprednol elaborate and dexamethasone in rabbits,” Current EyeResearch 11:525-30).

U.S. Pat. No. 5,501,856 discloses controlled-release pharmaceuticalpreparations for intraocular implants to be applied to the interior ofthe eye after a surgical operation for disorders in retinalvitreous bodyor for glaucoma.

U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic andhydrophobic entities in a biodegradable sustained release implant, anddescribes a polylactic acid polyglycolic acid (PLEA) copolymer implantcomprising dexamethasone. As shown by in vitro testing of the drugrelease kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implantdisclosed did not show appreciable drug release until the beginning ofthe fourth week.

U.S. Pat. No. 5,824,072 discloses implants for introduction into asuprachoroidal space or an avascular region of the eye, and describes amethylcellulose implant comprising dexamethasone.

U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocularimplants comprising microencapsulated drugs, and describes implantingmicrocapsules comprising hydrocortisone succinate into the posteriorsegment of the eye.

U.S. Pat. No. 5,164,188 discloses encapsulated agents for introductioninto the suprachoroid of the eye, and describes placing microcapsulesand plaques comprising hydrocortisone into the pars plana.

U.S. Pat. Nos. 5,443,505 and 5,766,242 discloses implants comprisingactive agents for introduction into a suprachoroidal space or anavascular region of the eye, and describes placing microcapsules andplaques comprising hydrocortisone into the pars plana.

Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine,triamcinolone, and human recombinant tissue plasminogen activator forintraocular management of proliferative vitreoretinopathy (PVR) (Zhou,T, et al. (1998). “Development of a multiple-drug delivery implant forintraocular management of proliferative vitreoretinopathy,” Journal ofControlled Release 55: 281-295.)

There is a continued need for efficacious intraocular sustained releasedrug therapies for patients with inflammatory conditions.

All references cited herein are hereby incorporated by reference intheir entirety.

DISCLOSURE OF THE INVENTION

The present invention provides a method for treating aninflammation-mediated condition of the eye, comprising: implanting intothe vitreous of the eye a bioerodible implant comprising a steroidalanti-inflammatory agent and a bioerodible polymer, wherein the implantdelivers the agent to the vitreous in an amount sufficient to reach aconcentration equivalent to at least about 0.05 μg/ml dexamethasonewithin about 48 hours and maintains a concentration equivalent to atleast about 0.03 μg/ml dexamethasone for at least about three weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting a solid body into the vitreous of the eye, said bodycomprising particles of a steroidal anti-inflammatory agent entrappedwithin a bioerodible polymer, whereby said agent is released from thebody by erosion of the polymer, and whereby said agent is delivered tothe vitreous at a rate and for a time sufficient to reach aconcentration equivalent to at least about 0.05 μg/ml dexamethasonewithin about 48 hours, and maintains a concentration equivalent to atleast about 0.03 μg/ml dexamethasone for at least about three weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting into the vitreous of the eye a bioerodible implant comprisinga steroidal anti-inflammatory agent and a bioerodible polymer, whereinthe implant delivers the agent to the vitreous in an amount sufficientto reach a concentration equivalent to at least about 0.2 μg/mldexamethasone within about 6 hours and maintains a concentrationequivalent to at least about 0.01 μg/ml dexamethasone for at least aboutthree weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting a solid body into the vitreous of the eye, said bodycomprising particles of a steroidal anti-inflammatory agent entrappedwithin a bioerodible polymer, whereby said agent is released from thebody by erosion of the polymer, and whereby said agent is delivered tothe vitreous at a rate and for a time sufficient to reach aconcentration equivalent to at least about 0.2 μg/ml dexamethasonewithin about 6 hours, and maintains a concentration equivalent to atleast about 0.01 μg/ml dexamethasone for at least about three weeks.

MODES FOR CARRYING OUT THE INVENTION Definitions

As used herein, the term “inflammation-mediated condition of the eye” ismeant to include any condition of the eye which may benefit fromtreatment with an anti-inflammatory agent, and is meant to include, butis not limited to, uveitis, macular edema, acute macular degeneration,retinal detachment, ocular tumors, fungal or viral infections,multifocal choroiditis, diabetic uveitis, proliferativevitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada(VKH) syndrome, histoplasmosis, and uveal diffusion.

The term “bioerodible polymer” refers to polymers which degrade in vivo,and wherein erosion of the polymer over time is required to achieve theagent release kinetics according to the invention. Specifically,hydrogels such as methylcellulose which act to release drug throughpolymer swelling are specifically excluded from the term “bioerodiblepolymer”. The terms “bioerodible” and “biodegradable” are equivalent andare used interchangeably herein.

The terms “steroidal anti-inflammatory agent” and “glucocorticoid” areused interchangeably herein, and are meant to include steroidal agents,compounds or drugs which reduce inflammation when administered at atherapeutically effective level.

“A concentration equivalent to dexamethasone”, as used herein, refers tothe concentration of a steroidal anti-inflammatory agent necessary tohave approximately the same efficacy in vivo as a particular dose ofdexamethasone. For example, hydrocortisone is approximatelytwentyfivefold less potent than dexamethasone, and thus a 25 mg dose ofhydrocortisone would be equivalent to a 1 mg dose of dexamethasone. Oneof ordinary skill in the art would be able to determine theconcentration equivalent to dexamethasone for a particular steroidalanti-inflammatory agent from one of several standard tests known in theart. Relative potencies of selected corticosteroids may be found, forexample, in Gilman, A. G., et al., eds. (1990). Goodman and Gilman's:The Pharmacological Basis of Therapeutics. 8th Edition, Pergamon Press:New York, p. 14417.

An “individual” is a vertebrate, preferably mammal, more preferably ahuman. Mammals include, but are not limited to, humans, sport animalsand pets, such as dogs, horses.

The terms “injury” or “damage” as used herein are interchangeable andrefer to the cellular and morphological manifestations and symptomsresulting from an inflammatory-mediated condition, such as, for example,inflammation.

The term “treating” as used herein, means to reduce or prevent ocularinjury or damage.

The term “therapeutic levels” as used herein, refers to the level ofagent needed to reduce or prevent ocular injury or damage.

By “measured under infinite sink conditions in vitro,” is meant assaysto measure drug release in vitro, wherein the experiment is designedsuch that the drug concentration in the receptor medium never exceeds 5%of saturation. Examples of suitable assays may be found, for example, in(USP 23; NF 18 (1995) pp. 1790-1798),

“A”, “an” and “the” include plural references unless the context clearlydictates otherwise.

Methods for Treating an Inflammation-Mediated Condition

Intraocular glucocorticoid drug delivery systems made of a biodegradablepolymer matrix have been developed which can release drug loads overvarious programmed time periods. These drug delivery systems which wheninserted into the vitreous provide therapeutic levels of glucocorticoidfor extended periods of time (e.g., 3 weeks or more). In particular,these delivery systems provide an initial “loading dose” level of drugof at least about 0.05 μg/ml dexamethasone equivalent to the posteriorsegment of the eye. These delivery systems have shown unexpected resultsin treating diseases such as uveitis and PVR.

Accordingly, the present invention provides a method for treating aninflammation-mediated condition of the eye, comprising: implanting intothe vitreous of the eye a bioerodible implant comprising a steroidalanti-inflammatory agent and a bioerodible polymer, wherein the implantdelivers the agent to the vitreous in an amount sufficient to reach aconcentration equivalent to at least about 0.05 μg/ml dexamethasonewithin about 48 hours and maintains a concentration equivalent to atleast about 0.03 μg/ml dexamethasone for at least about three weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting a solid body into the vitreous of the eye, said bodycomprising particles of a steroidal anti-inflammatory agent entrappedwithin a bioerodible polymer, whereby said agent is released from thebody by erosion of the polymer, and whereby said agent is delivered tothe vitreous at a rate and for a time sufficient to reach aconcentration equivalent to at least about 0.05 μg/ml dexamethasonewithin about 48 hours, and maintains a concentration equivalent to atleast about 0.03 μg/ml dexamethasone for at least about three weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting into the vitreous of the eye a bioerodible implant comprisinga steroidal anti-inflammatory agent and a bioerodible polymer, whereinthe implant delivers the agent to the vitreous in an amount sufficientto reach a concentration equivalent to at least about 0.2 μg/mldexamethasone within about 6 hours and maintains a concentrationequivalent to at least about 0.01 μg/ml dexamethasone for at least aboutthree weeks.

In another embodiment of the invention, a method for treating aninflammation-mediated condition of the eye is provided, comprising:implanting a solid body into the vitreous of the eye, said bodycomprising particles of a steroidal anti-inflammatory agent entrappedwithin a bioerodible polymer, whereby said agent is released from thebody by erosion of the polymer, and whereby said agent is delivered tothe vitreous at a rate and for a time sufficient to reach aconcentration equivalent to at least about 0.2 μg/ml dexamethasonewithin about 6 hours, and maintains a concentration equivalent to atleast about 0.01 μg/ml dexamethasone for at least about three weeks.

Preferred inflammation-mediated conditions of the eye which may betreated by the methods of the invention include uveitis, macular edema,acute macular degeneration, retinal detachment, ocular tumors, fungal orviral infections, multifocal choroiditis, diabetic uveitis,proliferative vitreoretinopathy (PVR), sympathetic opthalmia, VogtKoyanagi-Harada (VKH) syndrome, histoplasmosis, and uveal diffusion. Ina preferred embodiment, the inflammation-mediated condition of the eyeis uveitis. In another preferred embodiment, the inflammation-mediatedcondition of the eye is proliferative vitreoretinopathy (PVR).

The delivery systems are designed to release the glucocorticoid attherapeutic levels to the vitreous for a sustained period of time. Inone embodiment, the implant delivers the agent to the vitreous in anamount sufficient to reach a concentration equivalent to at least about0.05 μg/ml dexamethasone within about 48 hours. In other embodiments,the implant delivers the agent to the vitreous in an amount sufficientto reach a concentration equivalent to at least about 0.06 μg/ml, atleast about 0.07 μg/ml, at least about 0.08 μg/ml, at least about 0.1μg/ml, at least about 0.125 μg/ml, at least about 0.15 μg/mldexamethasone within about 48 hours.

In another embodiment, the implant delivers the agent to the vitreous inan amount sufficient to reach a concentration equivalent to at leastabout 0.2 μg/ml dexamethasone within about 6 hours. In otherembodiments, the implant delivers the agent to the vitreous in an amountsufficient to reach a concentration equivalent to at least about 0.3μg/ml, at least about 0.5 μg/ml, at least about 0.75 μg/ml, at leastabout 1.0 μg/ml, at least about 2.0 μg/ml dexamethasone within about 4hours, within about 6 hours, within about 8 hours, within about 10hours, within about 24 hours.

A concentration equivalent to at least about 0.01 μg/ml, at least about0.02 μg/ml, at least about 0.03 μg/ml, at least about 0.05 μg/ml, atleast about 0.07 μg/ml dexamethasone may be maintained for an extendedperiod of time (e.g., at least about three weeks.) The preferredconcentration levels of drug in the vitreous may vary according to theinflammatory mediated condition being treated. For treating uveitis, aconcentration equivalent of at least about 0.01 to 0.1 μg/mldexamethasone is preferred.

In one embodiment, said concentration is maintained for least about fourweeks. In other embodiments, said concentration is maintained for atleast about five weeks, at least about six weeks, at least about sevenweeks, at least about eight weeks, at least about nine weeks, at leastabout 10 weeks, at least about 12 weeks. The preferred duration of drugrelease may be determined by the inflammatory mediated condition beingtreated. For treating uveitis, a drug release duration of at least aboutthree weeks is preferable, more preferably at least about four weeks. Inone embodiment, more than one implant may be sequentially implanted intothe vitreous in order to maintain drug concentrations for even longerperiods.

The implants may be inserted into the eye by a variety of methods,including placement by forceps or by trocar following making a 2-3 ramincision in the sclera. The method of placement may influence the drugrelease kinetics. For example, implanting the device with a trocar mayresult in placement of the device deeper within the vitreous thanplacement by forceps, which may result in the implant being closer tothe edge of the vitreous. The location of the implanted device mayinfluence the concentration gradients of drug surrounding the device,and thus influence the release rates (e.g., a device placed closer tothe edge of the vitreous will result in a slower release rate).

Implants for Use in Treating Inflammatory-Mediated Conditions

The formulation of the implants for use in the invention may varyaccording to the preferred drug release profile, the particularglucocorticoid used, the condition being treated, and the medicalhistory of the patient.

The implants of the invention are formulated with particles of thesteroidal anti-inflammatory agent entrapped within the bioerodiblepolymer matrix. Release of the agent is achieved by erosion of thepolymer followed by exposure of previously entrapped agent particles tothe vitreous, and subsequent dissolution and release of agent. Therelease kinetics achieved by this form of drug release are differentthan that achieved through formulations which release drug throughpolymer swelling, such as with hydrogels such as methylcellulose. Inthat case, the drug is not released through polymer erosion, but throughpolymer swelling, which releases drug as liquid diffuses through thepathways exposed. The parameters which determine the release kineticsinclude the size of the drug particles, the water solubility of thedrug, the ratio of drug to polymer, the method of manufacture, thesurface area exposed, and the erosion rate of the polymer.

Preferably, the steroidal anti-inflammatory agent is selected from thegroup consisting of 21-acetoxypregnenolone, alclometasone, algestone,amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,clobetasol, clobetasone, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, fluclorinide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide. In a preferred embodiment, the steroidal anti-inflammatoryagent is selected from the group consisting of cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone. In a more preferred embodiment, the steroidalanti-inflammatory agent is dexamethasone. In another embodiment, thebioerodible implant comprises more than one steroidal anti-inflammatoryagent.

The implants may further comprise one or more additional therapeuticagents, such as antimetabolites and/or antibiotics. Antimetabolitesinclude, but are not limited to, folic acid analogs (e.g., denopterin,edatrexate, methotrexate, piritrexim, pteropterin, Tomudex®,trimetrexate), purine analogs (e.g., cladribine, fludarabine,6-mercaptopurine, thiamiprine, thioguanine), and pyrimidine analogs(e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil,gemcitabine, tegafur). Specific antibiotics include, but are not limitedto:

Antibacterial Antibiotics:

Aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycins,butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin,isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate,netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin,streptomycin, tobramycin, trospectomycin), amphenicols (e.g.,azidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins(e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin,

-lactams carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem,imipenem, meropenem, panipenem), cephalosporins (e.g., cefaclor,cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefcapenepivoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime,cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide,cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome,cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime,cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephalothin, cephapirin sodium,cephradine, pivcefalexin), cephamycins (e.g., cetbuperazone,cefmetazole, cefininox, cefotetan, cefoxitin), monobactams (e.g.,aztreonam, carumonam, tigemonam), oxacepherns, flomoxef, moxalactam),penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin,ampicillin, apalcillin, amoxicillin, azidocillin, azlocillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,carbenicillin carindacillin, clometocillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, fenbenicillin, floxacillin hetacillinlenampicillin, methampicillin, methicillin sodium, nafcillin sodium,oxacillin, penamecillin, penethamate hydroiodide, penicillin gbenethamine, penicillin g benzathine, penicillin g benzhydrylamine,penicillin g calcium, penicillin g hydrabamine, penicillin g potassium,penicillin g procaine, penicillin n, penicillin o, penicillin v,penicillin v benzathine, penicillin v hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,ticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin,lincomycin), macrolides azithromycin, carbomycin, clarithromycin,dirithromycin, erythromycin, erythromycin acistrate, erythromycinestolate, erythromycin glucoheptonate, erythromycin lactobionate,erythromycin propionate, erythromycin stearate, josamycin, leucomycins,midecamycins, miokamycin, oleandomycin, primycin, rokitamycin,rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides(e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin,enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin,polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton,tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin,virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline,chlortetracycline, clomocycline, demeclocycline, doxycycline,guamecycline, lymecycline, meclocycline, methacycline, minocycline,oxytetracycline, penimepicycline, pipacycline, rolitetracycline,sancycline, tetracycline), and others (e.g., cycloserine, mupirocin,tuberin).

Synthetic Antibacterials:

2,4-Diaminopyrimidines (e.g., brodimoprim, tetroxoprim, trimethoprim),nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene,nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol,nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin,clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine,grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid,norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin,pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin,temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (e.g., acetylsulfamethoxypyrazine, benzylsulfamide, chloramine-b, chloramine-t,dichloramine t, n²-formylsullisomidine, n⁴-

-d-glucosylsulfanilamide, mafenide, 4′-(methylsulfamoypsulfanilanilide,nopryisulfamide, phthalylsulfacetatnide, phthalylsulfathiazole,salazosulfadimidine, succinylsulfathiazole, sulfabenzamide,sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine,sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine,sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid,sulfamerazine, sulfameter, sulfamethazine, sulfamethizole,sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine,sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n⁴-sulfanilyisulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone,acediasulfone, acetosulfone sodium, dapsone, diathymosulfone,glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid,p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others(e.g., clofoctol, hexedine, methenamine, methenamineanhydromethylene-citrate, methenamine hippurate, methenamine mandelate,methenamine sulfosalicylate, nitroxoline, taurolidine, xibornol).

Antifungal Antibiotics:

Polyenes (e.g., amphotericin b, candicidin, dermostatin, filipin,fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin,nystatin, pecilocin, perimycin), others (e.g., azaserine, griseofulvin,oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin,viridin).

Synthetic Antifungals:

Allylamines (e.g., butenafine, naftifine, terbinafine), imidazoles(e.g., bifonazole, butoconazole, chlordantoin, chlormidazole,cloconazole, clotrimazole, econazole, enilconazole, fenticonazole,flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole,omoconazole, oxiconazole nitrate, sertaconazole, sulconazole,tioconazole), thiocarbamates (e.g., tolciclate, tolindate, tolnaftate),triazoles (e.g., fluconazole, itraconazole, saperconazole, terconazole)others (e.g., acrisorcin, amorolfine, biphenamine,bromosalicylchloranilide, buclosamide, calcium propionate,chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazoledihydrochloride, exalamide, flucytosine, halethazole, hexetidine,loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione,salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin,ujothion, undecylenic acid, zinc propionate).

Antineoplastic:

Antibiotics and analogs (e.g., aclacinomycins, actinomycin f₁,anthramycin, azaserine, bleomycins, cactinomycin, carubicin,carzinophilin, chromomycins, dactinomycin, daunorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, eptrubicin, idarubicin,menogaril, mitomycins, mycophenolic acid, nogalamycin, olivomycines,peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin,streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin),antimetabolites (e.g. folic acid analogs (e.g., denopterin, edatrexate,methotrexate, piritrexim, pteropterin, Tomudex®, trimetrexate), purineanalogs (e.g., cladribine, fludarabine, 6-mercaptopurine, thiamiprine,thioguanine), pyrimidine analogs (e.g., ancitabine, azacitidine,6-azauridine, carmofur, cytarabine, doxifluridine, emitefur,enocitabine, floxuridine, fluorouracil, gemcitabine, tagafur).

The steroidal anti-inflammatory agent is preferably from about 10 to 90%by weight of the implant. More preferably, the agent is from about 50 toabout 80% by weight of the implant. In a preferred embodiment, the agentcomprises about 50% by weight of the implant, in a particularlypreferred embodiment, the agent comprises about 70% by weight of theimplant.

The implants are preferably monolithic, i.e. having the glucocorticoidhomogenously distributed through the polymeric matrix. The selection ofthe polymeric composition to be employed will vary with the desiredrelease kinetics, patient tolerance, the nature of the disease to betreated and the like. Characteristics of the polymers will includebiodegradability at the site of implantation, compatibility with theagent of interest, ease of encapsulation, water insolubility, and thelike. Preferably, the polymeric matrix will not be fully degraded untilthe drug load has been released. The polymer will usually comprise atleast about 10, more usually al least about 20 weight percent of theimplant.

Biodegradable polymeric compositions which may be employed may beorganic esters or ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Anhydrides,amides, orthoesters or the like, by themselves or in combination withother monomers, may find use. The polymers will be condensationpolymers. The polymers may be cross-linked or non-cross-linked, usuallynot more than lightly cross-linked, generally less than 5%, usually lessthan 1%. For the most part, besides carbon and hydrogen, the polymerswill include oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen may be present as amide, cyano and amino. The biodegradablepolymers set forth in Heller, Biodegradable Polymers in Controlled DrugDelivery, in: CRC Critical Reviews in Therapeutic Drug Carrier Systems,Vol. 1. CRC Press, Boca Raton, Fla. (1987), may be used.

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. By employing the L-lactate or D-lactate, a slowly biodegradingpolymer is achieved, while degradation is substantially enhanced withthe racemate. Copolymers of glycolic and lactic acid are of particularinterest, where the rate of biodegradation is controlled by the ratio ofglycolic to lactic acid. The % of polylactic acid in the polylactic acidpolyglycolic acid (PLGA) copolymer can be 0-100%, preferably about15-85%, more preferably about 35-65%. In a particularly preferredembodiment, a 50/50 PLGA copolymer is used. The most rapidly degradedcopolymer has roughly equal amounts of glycolic and lactic acid, whereeither homopolymer is more resistant to degradation. The ratio ofglycolic acid to lactic acid will also affect the brittleness of in theimplant, where a more flexible implant is desirable for largergeometries. The size of the polymer particles is preferably about 1-100μm in diameter, more preferably about 5-50 μm in diameter, morepreferably about 9-12 μm in diameter, still more preferably about 10 μmin diameter.

Among the polysaccharides of interest are calcium alginate, andfunctionalized celluloses, particularly carboxymethylcellulose esterscharacterized by being biodegradable, water insoluble, a molecularweight of about 5 kD to 500 kD, etc.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of theglucocorticoid in the absence of modulator.

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Water soluble preservatives which may be employed includesodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. These agents may be present in individual amounts of from about0.001 to about 5% by weight and preferably about 0.01 to about 2%.Suitable water soluble buffering agents that may be employed are sodiumcarbonate, sodium borate, sodium phosphate, sodium acetate, sodiumbicarbonate, etc., as approved by the FDA for the desired route ofadministration. These agents may be present in amounts sufficient tomaintain a pH of the system of between 2 to 9 and preferably 4 to 8. Assuch the buffering agent may be as much as 5% on a weight to weightbasis of the total composition. Electrolytes such as sodium chloride andpotassium chloride may also be included in the formulation. Where thebuffering agent or enhancer is hydrophilic, it may also act as a releaseaccelerator. Hydrophilic additives act to increase the release ratesthrough faster dissolution of the material surrounding the drugparticles, which increases the surface area of the drug exposed, therebyincreasing the rate of drug bioerosion. Similarly, a hydrophobicbuffering agent or enhancer dissolve more slowly, slowing the exposureof drug particles, and thereby slowing the rate of drug bioerosion.

The proportions of glucocorticoid, polymer, and any other modifiers maybe empirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp,1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration is after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly tomaintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

The release kinetics of the drug delivery devices of the invention aredependent in part on the surface area of the devices. Larger surfacearea exposes more polymer to the vitreous, causing faster erosion anddissolution of the drug particles entrapped by the polymer. The size andform of the implant can be used to control the rate of release, periodof treatment, and drug concentration at the site of implantation. Largerimplants will deliver a proportionately larger dose, but depending onthe surface to mass ratio, may have a slower release rate. The implantsmay be particles, sheets, patches, plaques, films, discs, fibers,microcapsules and the like and may be of any size or shape compatiblewith the selected site of insertion, as long as the implants have thedesired release kinetics. Preferably, the implant to be inserted isformulated as a single particle. Preferably, the implant will notmigrate from the insertion site following implantation. The upper limitfor the implant size will be determined by factors such as the desiredrelease kinetics, toleration for the implant, size limitations oninsertion, ease of handling, etc. The vitreous chamber is able toaccommodate relatively large implants of varying geometries, havingdiameters of 1 to 3 mm in a preferred embodiment, the implant is acylindrical pellet (e.g., rod) with dimensions of about 2 mm×0.75 mmdiameter. The implants will also preferably be at least somewhatflexible so as to facilitate both insertion of the implant in thevitreous and accommodation of the implant. The total weight of theimplant is preferably about 250-5000 μg, more preferably about 500-1000μg. In one embodiment, the implant is about 500 μg. In a particularlypreferred embodiment, the implant is about 1000 μg.

In a preferred embodiment, a solid bioerodible implant for treating aninflammation-mediated condition of the eye is provided, consistingessentially of: dexamethasone particles entrapped within a polylacticacid polyglycolic acid (PLGA) copolymer, wherein the implant comprisesabout 70 percent by weight of dexamethasone and about 30 percent byweight of PLGA, wherein the total mass of the implant is about 800-1100μg, and wherein the implant releases at least about 10% of the drug loadwithin 1 week when measured under infinite sink conditions in vitro. Ina more preferred embodiment, the total mass of the implant is about 1000μg. In other embodiments, the implant releases at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, of the drug load within 1 week when measured under infinite sinkconditions in vitro. In other embodiments, the implant releases at leastabout 15%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, of the drug load within 2 weeks when measured underinfinite sink conditions in vitro.

Methods for Making the Implants of the Invention

Various techniques may be employed to produce the implants. Usefultechniques include phase separation methods, interfacial methods,extrusion methods, compression methods, molding methods, injectionmolding methods, heat press methods and the like.

Choice of the technique, and manipulation of the technique parametersemployed to produce the implants can influence the release rates of thedrug. Room temperature compression methods result in an implant withdiscrete microparticles of drug and polymer interspersed. Extrusionmethods result in implants with a progressively more homogenousdispersion of the drug within the polymer, as the production temperatureis increased. When using extrusion methods, the polymer and drug arechosen to as to be stable at the temperatures required formanufacturing, usually at least about 85° C. Extrusion methods usetemperatures of about 25° C. to about 150° C., more preferably about 65°C. to about 130° C. Generally, compression methods yield implants withfaster release rates than extrusion methods, and higher temperaturesyield implants with slower release rates.

In a preferred embodiment, compression methods are used to produce theimplants of the invention. Preferably, compression methods use pressuresof 50-150 psi, more preferably about 70-80 psi, even more preferablyabout 76 psi, and use temperatures of about 0° C. to about 115° C., morepreferably about 25° C. In another preferred embodiment, extrusionmethods are used. Preferably, implants produced by extrusion methods areheated to a temperature range of about 60° C. to about 150° C. fordrug/polymer mixing, more preferably about 130° C., for a time period ofabout 0 to 1 hour, 0 to 30 minutes, 5-15 minutes, preferably about 10minutes, preferably about 0 to 5 min. Preferably, the implants are thenextruded at a temperature of about 60° C. to about 130° C., morepreferably about 75° C.

Kits for the Administration of the Implants

In another aspect of the invention, kits for treating aninflammation-mediated condition of the eye are provided, comprising: a)a container comprising a bioerodible implant comprising dexamethasoneand polylactic acid polyglycolic acid (PLGA) copolymer in a ratio ofabout 70/30; and b) instructions for use.

The invention is further illustrated by the following nonlimitingexamples.

EXAMPLES Example 1: Manufacture and In Vitro Testing of BioerodibleDexamethasone Posterior Segment Drug Delivery System (DEX PS DDS®)

2100 mg of dexamethasone powder (Upjohn) (particle sizes less than 10 μmin diameter) were mixed with 900 mg of 50/50 polylactic acidpolyglycolic acid (PLGA) (particle sizes approximately 9-12 μm indiameter) at ambient temperature. A small Teflon® tube was filled with900-1100 μg of the above mixture, and placed directly on the die cavity.The powder was pushed out of the tubing into the die cavity with astainless steel wire and the tube and wire were removed from the die.The powder was pressed using a tablet press (approximately 76 psi),ejected with the ejector switch, and removed with tweezers. Theresulting pellet was approximately 2 mm×0.75 mm.

Release of dexamethasone from the DEX PS DDS® system was measured. OneDDS was placed in a glass vial filled with receptor medium (0.9% NaCl inwater). To allow for “infinite sink” conditions, the receptor mediumvolume was chosen so that the concentration would never exceed 5% ofsaturation. To minimize secondary transport phenomena, e.g.concentration polarization in the stagnant boundary layer, the glassvial was placed into a shaking water bath at 37° C. Samples were takenfor HPLC analysis from the vial at defined time points. The HPLC methodwas as described in USP 23(1995) pp. 1791-1798. The concentration valueswere used to calculate the cumulative release data, as shown in Table 1.

TABLE 1 DEX PS DDS ® In vitro Release Day % Total Release 1 10.1 2 16.47 39.4 14 55.5 21 69.3 28 80.7 35 88.1

Table 1 shows an almost linear in vitro release of dexamethasone over aone month period of time.

Example 2: In Vivo Testing of DEX PS DDS® in Rabbits

One DEX PS DDS® per eye was implanted into the vitreous of four rabbitswith forceps. The in vivo vitreous concentrations of dexamethasone ineach of the four eyes were monitored by vitreous sampling. For example,at day 2 the concentrations measured were 0.03 μg/ml, 0.1 μg/ml and 0.19μg/ml. The concentrations in each of the four eyes were measured on days2, 7, 21, 28 and 35; the average results are summarized in Table 2. Thevolume of rabbit eyes is approximately 60-70% percent that of humaneyes.

TABLE 2 In vivo concentrations of dexamethasone (DDS placed withforceps) Day μg/ml 2 0.16 ± 0.13 7 0.15 ± 0.16 21 0.08 ± 0.07 28 0.005 ±0.01  35 0.037 ± 0.03 

The same DDS was tested to vivo in rabbits, wherein the DDS was placedto a depth of about 5-10 mm in the vitreous with trocar. The levels ofdexamethasone in the vitreous are shown in Table 3.

TABLE 3 In vivo concentrations of dexamethasone (DDS placed with trocar)Sample ID 5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-SHours Sample Conc., ug/ml Avg SD 2 0.56 3.07 1.82 1.77 4 5.48 6.95 6.221.04 6 2.08 5.15 3.62 2.17 24 2.33 2.69 2.51 0.25 Animal#/ DDS wt. Dexwt. Dex ug/mL day ug ug 2 7 14 21 28 35 21427-D 990 693 2.29 21427-S1023 715.1 1.56 21433-D 804 562.8 1.2 21433-S 1057 739.9 0.77 21428-D1003 702.1 9.26 21428-S 1025 717.5 0.35 21434-D 863 604.1 3.31 21434-S1106 774.2 0.84 21429-D 1013 709.1 n/a 21429-S 977 648.9 0.19 21435-D1104 772.8 0.43 21435-S 941 658.7 0.11 21432-D 860 692 0.43 21432-S 941685.7 1.72 21436-D 1010 707 0.31 21436-S 1054 737.8 0.13 21431-D 996697.2 0.52 21431-S 918 642.6 1.15 21437-D 1049 732.9 0.19 21437-D 1075752.5 0.48 21430-D 994 695.8 0.06 21430-S 1086 760.2 0.18 21438-D 974681.8 0.03 21438-S 831 581.7 8.35 Ave. 985.17 694.43 1.46 3.44 0.24 0.650.59 2.16 * Unable to determine due to insufficient sample

The data indicate that the DEX PS DDS® releases dexamethasone to thevitreous in concentrations above 0.01 μg/ml for an extended period oftime. Further, the data indicate that placement of the device withtrocar results in much higher levels of drug release than with placementwith forceps, most likely due to placement of the device deeper withinthe vitreous. The data at two, four, six, and 24 hours in Table 3 showsan initial spike of drug release.

Example 3: Treatment of Severe Uveitis in Human Patients with DEX PSDDS®

Three eyes of two patients (ages 5 and 55 years) with severe progressiveuveitis were treated with the DEX PS DDS®. The use of the DEX PS DDS® incompassionate and emergency use situations was conducted under aninvestigative new drug application (IND) with the U.S. F.D.A. A writteninformed consent was obtained from the participating patients.

Subjects in this study underwent pars plana vitrectomy. Immediatelyafter the vitrectomy, the DEX PS DDS® was inserted into the vitreouscavity through the pars plana. The DDS pellet appeared to remain in thelocation where it was placed, and released the drug over at leastapproximately 4-5 weeks.

Patient #1 was a 55-year-old female who initially presented with opticneuritis in 1990. This patient subsequently developed recurrentposterior uveitis secondary to inflammatory polyarthritis. Response tosystemic and periocular steroid treatment was intermittent. Methotrexateand cyclosporine were found to be effective, however, these drugsinduced severe side effects. Methotrexate caused elevated liver enzymesand pancreatitis. The patient developed pustular dermatitis withcyclosporine treatment. Cytoxan was subsequently used, bothintravenously and orally, with satisfactory initial results. Later, theinflammatory polyarthritis was controlled with Gold injections. Thepatient's Type I diabetes was well controlled and the pancreatitisresolved.

The patient was referred to us in September 1998 for further evaluationand treatment of uveitis due to progressive visual loss and lack ofresponse to conventional medications. A vitrectomy had been performed onher left eye several years earlier for treatment of uveitis. Visualacuity in both eyes was counting fingers. Intraocular pressure in botheyes was 20 mm Hg. Slit lamp exam of the right anterior chamber revealedtrace flare and 1-5 cells. Examination of the left anterior chamberrevealed no flare and 8-9 cells. A mild nuclear sclerotic cataract waspresent in the right eye and a moderate one was noted in the left eye.In the anterior vitreous of the right eye, 50-100 fine cells werepresent. There were 6-7 cells in the left anterior vitreous.

On ophthalmoscopy of the right eye, the vitreous was hazy and a poorview was obtained. It was possible to see a peripapillary scar andnumerous histoplasmosis type retinal scars 360° from the posterior poleout to the periphery. In the left eye, the vitreous was not as hazy andthe retina appearance was very similar to that of the right eye. Theright eye was selected for initial treatment due to its more acuteinvolvement and the more severe inflammatory response.

In October 1998, a standard three port system pars plana vitrectomy wasperformed and the DEX PS DDS® was inserted through the pars plana. Atthe end of surgery, the patient received periocular celestone suspension1 cc (β-methasone sodium phosphate/β-methrazone acetate,Schering-Plough) and periocular gentamicin 0.1 cc (Abbott Laboratories).Topical medications consisting of Tobradex® (tobratnycin/dexamethasone,Alcon Labs) and Cyclogyl® 1% drops (cyclopentolate HCl, Alcon Labs)q.i.d. were prescribed. The retina was clearly seen for the first timeduring surgery after removal of the vitreous. There was a peripapillaryscar and numerous healed histoplasmosis type scars 360° from theposterior pole to the periphery. In addition, there were several smallretinal hemorrhages that appeared to be consistent with diabeticretinopathy. No active inflammatory retinitis or choroiditis was seen. Amild amount of epiretinal gliosis was present at six o'clock in themid-periphery. There was no evidence of snowbanking or snowballopacities.

The first (right) eye of patient #1 improved from counting fingers to20/200 on the first day postoperatively. The best vision was 20/40 atsix months. One year acuity was 20/50 and at the last visit (16 months)the vision was 20/60 (Table 3).

TABLE 4 Patient 1: Right Eye Visual Acuity Visual Acuity PreOp CF Day 1 20/200 Month 1  20/200 Month 2 20/80 Month 3 20/60 Month 4 20/40 Month5 20/50  Month 16 20/60

Postoperatively, anterior chamber flare varied between 0 and trace andcells varied between 1 and 6. Vitreous flare varied between 0 and trace.Vitreous cells varied between 0 and 20.

On ophthalmoscopy, the vitreous and retina were found to remaincompletely quiet. The DEX PS DDS® implant was resorbed at approximatelyfive weeks. The retinal hemorrhages disappeared. There was no detectableincrease in the patient's cataract. Fluorescein angiography did notreveal any evidence of macular edema. Present eye medications consist ofAcular® (ketorolac promethamine 0.5%, Allergan) drops q.i.d.

After it was determined that favorable results were achieved in theright eye, the patient received the same treatment for the left eye inApril 1999. The left eye presented very similarly to the right eye,other than a more significant cataract and the uveitis being morechronic in nature. Notably, a pars plana vitrectomy had been performedon this eye for this condition 3 years previously.

The second (left) eye of patient #1 initially improved to a visualacuity of 20/400 (3 months postoperatively), but later returned tocounting fingers (7.5 months). This decline in visual acuity appeared tobe secondary to progression of the cataract. Postoperatively (first 10months), on slit lamp examination, anterior chamber flare varied from 0to moderate and cells varied from 0 to >30. Vitreous flare varied from 0to severe and vitreous cells varied from 0 to >250. On the last visit(11 months), there was no AC flare or cells, and vitreous detail was notobserved due to cataract There had been no vitreous flare or cellsdetected on the previous visit (10 months). Visual acuity at 11 monthswas counting fingers. Present eye medications consist of Acular® dropsq.i.d.

Patient #2 is a 5-year-old male with an eight month history of bilateralpars planitis. The right eye was mild and stable, but the left eye wasprogressive and severe with only transient response to topical andsubtenon steroids. This was an idiopathic uveitis. The patient developedcomplications in the left eye including decreased vision to 20/200, aposterior subcapsular cataract, band keratopathy, and glaucoma withintraocular pressures in the low 30's. There was mild flare and 20 cellsin the anterior chamber.

The anterior vitreous was very prominent and the cells were too numerousto count. On ophthalmoscopy, the patient was found to have snowballvitreous opacities, snowbanking, and peripheral retinoschisis or a lowretinal detachment, Multiple uveitis consultations offered treatmentchoices of systemic steroids, systemic antimetabolites, and pars planavitrectomy. Because of the patient's young age and potential sideeffects of systemic treatments, it was elected to perform a pars planavitrectomy. The surgery was carried out uneventfully in September 1999.The treatment consisted of a pars plana vitrectomy, insertion of DEX PSDDS®, and transconjunctival cryopexy.

Patient #2 had a one day postoperative visual acuity of 20/400 and thebest vision was 20/70 (Table 4).

TABLE 5 Patient 2: Left Eye Visual Acuity Visual Acuity PreOp  20/200Month 1 20/70 Month 2  20/100 Month 3 20/70 Month 4 20/80 Month 5 20/100 Month 6 20/80

Visual acuity at five months decreased to 20/100 secondary toprogression of the posterior subcapsular cataract. On slit lampexamination, anterior chamber flare varied between 0 to mild and cellsvaried from 0 to 4. Vitreous flare was 0 and vitreous cells varied from0 to 10. On ophthalmoscopy, a mild amount of residual snowballs andsnowbanking was evident. The peripheral retinal detachment/schisishealed well and was flat. The eye responded very well with the exceptionof intraocular pressure. Pressures were in the teens up to the 20's inthe immediate postoperative period, and after two months the pressurewent up to 44 mm A glaucoma consultation was obtained and it wasconcluded that the intraocular pressure increase was due to the topicalantibiotic steroid combination drops used postoperatively. Themedications were terminated and the patient was prescribed topicalanti-glaucoma medication. The last postoperative pressure measurement (6months) was 13 mm Hg. There is no evidence of damage to the optic nerve.Present medications consist of Timoptic® 0.25% (timolol maleate, FalconPharmaceuticals), Acular®, and Vexol®) 1% (rimexolone, Alcon Labs) allb.i.d.

Outcomes for these two patients suggest that DEX PS DDS® may be veryeffective in the treatment of severe uveitis. It appears that the DEX PSDDS® is well tolerated, and that the one month drug delivery system canbe effective over a much longer period of time in treating these chronicuveitis patients.

Example 4: Treatment of Severe and Recalcitrant Uveitis in HumanPatients with DEX PS DOS®

Four eyes of 4 patients who have had failed treatments for severeuveitis were treated with the DEX PS DDS®. Subjects in this studyunderwent a standard 3 port pars plana vitrectomy. Immediately after thevitrectomy, the DEX PS DDS® was inserted into the vitreous cavitythrough the pars plana. The DDS pellet appeared to remain in thelocation where it was placed, and released the drug over approximately 1month.

Three patients had a single procedure with DEX PS DDS® insertion and 1patient had a second DEX PS DDS® insertion when surgery was requiredfrom complications of the disease. All patients have shown a remarkableresponse to the medication and vision in all patients has improved. Thebeginning vision was as low as counting fingers only and the improvementhas been as high as 20/30. With 2-22 months follow up all patients haveresponded positively and there have been no new recurrences. The patientwho had 2 insertions has shown complete regression of the disease.

Example 5. Use of DEX PS DDS® in the Treatment of Recurrent RetinalDetachment

The effect of DEX PS DDS® as an adjunct in the treatment of recurrentretinal detachments associated with PVR was evaluated. Six eyes of sixpatients with 2-4 previous retinal procedures and who had recurrence dueto PVR were treated with DEX PS DDS®, which was inserted into thevitreous cavity after a standard 3 port pars plana vitrectomy withmembrane peeling, endolaser, and air-fluid-gas or silicone oil exchange,with or without a scleral buckle.

Four patients had surgery with reattachment with one operation. Twopatients had a second procedure due to initial incomplete removal of theexisting PVR. With the second procedure the retina of one patient hasremained attached. The second patient has developed recurrent PVR andre-detachment and will undergo further surgery. With 3-13 monthsfollow-up five retinas were attached with no new PVR.

The DEX PS DDS® appeared to be very effective in the treatment of PVRrelated retinal detachments.

Example 6: Manufacture and In Vitro Testing of 50/50 Dexamethasone/PLGAPosterior Segment Drug Delivery System

2.5 g of PLGA (particle sizes approximately 9-12 μm in diameter) wereplaced in a mixing vessel. The vessel was placed in the oven (130° C.)for ten minutes. 2.5 g of dexamethasone (particle sizes less thanapproximately 10 μm in diameter) were added to the vessel, and thevessel was returned to the oven for 10 minutes. The PLGA/dexamethasonemixture was mixed well, the blend loaded into a barrel and 650-790 μmdiameter filaments extruded. The resulting filaments were cut intolengths of approximately 0.94 and 1.87 mm for the 500 μg and 1000 μgformulations, respectively.

Release of dexamethasone from the 50/50 dexamethasone/PLGA DDSformulations were measured. One DDS was placed in a glass vial filledwith receptor medium (0.9% NaCl in water). To allow for “infinite sink”conditions, the receptor medium volume was chosen so that theconcentration would never exceed 5% of saturation. To minimize secondarytransport phenomena, e.g. concentration polarization in the stagnantboundary layer, the glass vial was placed into a shaking water bath at37° C. Samples were taken for HPLC analysis from the vial at definedtime points. The HPLC method was as described in USP 23(1995) pp.1791-1798. The concentration values were used to calculate thecumulative release data, as shown in Table 6.

TABLE 6 In vitro release of 50% Dex-PS (0.5 mg formulation) Dex ug DayRelease/day % Total release 50% Dex PS 0.5 mg system replicate 1 1 3.001.41 7 1.99 7.93 13 0.90 13.43 20 1.79 30.21 27 1.54 49.77 34 1.93 80.5241 0.24 85.05 48 0.24 90.38 55 0.10 93.00 62 0.15 97.44 69 0.07 99.84 760.07 102.25 50% Dex PS 0.5 mg system replicate 2 1 6.00 2.17 7 1.66 6.3813 0.99 11.05 20 1.21 19.82 27 2.29 42.23 34 2.34 71.05 41 0.44 77.54 480.29 82.61 55 0.14 85.34 62 0.20 89.80 69 0.10 92.21 76 0.06 84.38 50%Dex PS 0.5 mg system replicate 3 1 5.70 3.27 7 1.11 7.71 13 0.83 13.8320 0.05 14.47 27 1.63 39.63 34 1.52 69.26 41 0.21 74.10 48 0.19 79.23 550.08 81.69 62 0.14 86.58 69 0.07 89.46 76 0.06 92.26

TABLE 7 In vitro release of 50% Dex-PS (1 mg formulation) Dex ug DayRelease/day % Total release 50% Dex PS 1 mg system replicate 1 1 6.901.28 7 3.48 5.78 13 1.93 10.43 20 3.46 23.22 27 3.74 41.89 34 3.94 66.8341 1.79 80.17 48 1.28 91.49 55 0.21 93.59 62 0.24 96.39 69 0.11 97.85 760.09 99.11 50% Dex PS 1 mg system replicate 2 1 3.90 0.71 7 2.26 3.62 131.66 7.57 20 3.14 19.09 27 4.32 40.48 34 4.06 65.77 41 1.61 77.90 481.34 89.70 55 0.19 91.60 62 0.23 94.18 69 0.10 95.50 76 0.09 96.78 50%Dex PS 1 mg system replicate 3 1 4.50 0.91 7 2.16 3.98 13 1.69 8.42 201.25 13.48 27 3.88 34.67 34 3.53 58.97 41 1.85 74.28 48 0.88 82.85 550.19 84.94 62 0.26 88.15 69 0.11 89.75 76 0.10 91.26

Example 7: In Vivo Testing of 50/50 Dexamethasone/PLGA 1 mg Formulationsin Rabbits

One 50/50 dexamethasone/PLGA 1 mg formulation DDS per eye was implantedinto the vitreous of 6 rabbits using a trocar. The DDS was loaded intothe trocar, a hole was punched through the sclera, the trocar insertedthrough the hole, and the trocar plunger depressed to insert the DDSinto the vitreous. In vivo vitreous concentrations of dexamethasone weremonitored, as shown in Table 8.

TABLE 8 In vivo vitreous concentrations of dexamethasone Sample ID5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-S Hours SampleConc., ug/ml Avg SD 2 1.38 1.69 1.54 0.22 4 2.16 0.96 0.47 0.37 6 0.730.21 0.47 0.37 24 0.57 0.74 0.66 0.12 Animal#/ Dex ug/mL day 7 21 35 4963 2953-D 0.5 0.58 2953-S 0.11 0.69 2952-D 0.13 1.2 2952-S 0.12 0.552946-D 0.19 2.55 2946-S * 3     0.14 2949-D * 5.44   0.28 2949-S  0.02480.01 2982-D 1.087 2982-S 0.058 2983-D 0.018 2983-S 0.045 Ave. 0.22 2.160.30 0.76 0.75 * High level was due to the surgical artifact

The data indicate that the 50/50 dexamethasone/PLGA DDS releasesdexamethasone to the vitreous in concentrations above 0.01 μg/ml for anextended period of time. The data at two, four, six, and 24 hours inTable 8 shows an initial spike of drug release, due to drug which isunencapsulated by the delivery system.

The 100-120 μg 50/50 PLGA/dexamethasone implant disclosed in U.S. Pat.No. 5,869,079 shows similar in vitro release kinetics to the 500 and1000 μg 50/50 PLGA/dexamethasone implant disclosed herein. However, thepreviously disclosed implant would not provide drug concentrations inthe vitreous at the levels described herein.

Modifications of the above described modes for carrying out theinvention that are obvious to those of ordinary skill in the surgical,pharmaceutical, or related arts are intended to be within the scope ofthe following claims.

What is claimed is:
 1. A method for treating an inflammation-mediatedcondition of the eye comprising: implanting into the vitreous of an eyein need thereof a bioerodible implant comprising a steroidalanti-inflammatory agent and a bioerodible polymer, wherein the implantis produced by an extrusion method, wherein the total weight of theimplant is about 500-1000 μg, and wherein the inflammation-mediatedcondition of the eye is macular edema.
 2. The method of claim 1, whereinthe bioerodible polymer is a polylactic acid polyglycolic acid (PLGA)copolymer.
 3. The method of claim 2, wherein the PLGA copolymer is a50/50 PLGA copolymer.
 4. The method of claim 2, wherein the steroidalanti-inflammatory agent comprises about 10% to 90% by weight of theimplant.
 5. The method of claim 4, wherein the steroidalanti-inflammatory agent comprises about 50% to about 80% by weight ofthe implant.
 6. The method of claim 5, wherein the steroidalanti-inflammatory agent is dexamethasone.